Molecular portraits and trastuzumab responsiveness of estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancer

Abstract

<b>Background</b>: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. <b>Methods</b>: We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. <b>Results</b>: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower <i>TP53</i> mutation rate (30% vs. 69%, <i>P</i> < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. <b>Conclusions</b>: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.